US7452899B2 - Gamma-secretase inhibitors - Google Patents

Gamma-secretase inhibitors Download PDF

Info

Publication number
US7452899B2
US7452899B2 US10/566,486 US56648604A US7452899B2 US 7452899 B2 US7452899 B2 US 7452899B2 US 56648604 A US56648604 A US 56648604A US 7452899 B2 US7452899 B2 US 7452899B2
Authority
US
United States
Prior art keywords
alkyl
halogen
fluorophenyl
mmol
compounds
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related, expires
Application number
US10/566,486
Other languages
English (en)
Other versions
US20060189666A1 (en
Inventor
Michela Bettati
Amanda Louise Boase
Ian Churcher
Tamara Ladduwahetty
Kevin John Merchant
Abdul Quddus
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Organon Pharma UK Ltd
Original Assignee
Merck Sharp and Dohme Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck Sharp and Dohme Ltd filed Critical Merck Sharp and Dohme Ltd
Assigned to MERCK SHARP & DOHME LTD. reassignment MERCK SHARP & DOHME LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: QUDDUS, ABDUL, LADDUWAHETTY, TAMARA, BOASE, AMANDA LOUISE, BETTATI, MICHELA, CHURCHER, IAN, MERCHANT, KEVIN JOHN
Publication of US20060189666A1 publication Critical patent/US20060189666A1/en
Application granted granted Critical
Publication of US7452899B2 publication Critical patent/US7452899B2/en
Expired - Fee Related legal-status Critical Current
Adjusted expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to a novel class of compounds, their salts, pharmaceutical compositions comprising them, processes for making them and their use in therapy of the human body.
  • the invention relates to novel sulphonamide and sulphamide derivatives which inhibit the processing of APP by ⁇ -secretase, and hence are useful in the treatment or prevention of Alzheimer's disease.
  • AD Alzheimer's disease
  • a ⁇ ⁇ -amyloid peptide
  • WO 01/70677 and WO 02/36555 disclose, respectively, sulphonamido- and sulphamido-substituted bridged bicycloalkyl derivatives which are believed to be useful in the treatment of Alzheimer's disease, but do not disclose or suggest compounds in accordance with the present invention.
  • the present invention provides a novel class of bridged bicycloalkyl sulphonamide and sulphamide derivatives which show a particularly strong inhibition of the processing of APP by the putative ⁇ -secretase, and thus are useful in the treatment or prevention of AD.
  • n 0 or 1
  • X completes a 5- or 6-membered heteroaromatic ring bearing the group Ar as a substituent, and also the group R 5 as a substituent when n is 1;
  • R 5 represents a hydrocarbon group of 1-5 carbon atoms which is optionally substituted with up to 3 halogen atoms;
  • Ar represents phenyl or 6-membered heteroaryl, either of which bears 0-3 substituents independently selected from halogen, CF 3 , CHF 2 , CH 2 F, NO 2 , CN, OCF 3 , C 1-6 alkyl and C 1-6 alkoxy;
  • Y represents a bond or NR 3 ;
  • R 1 represents H, or when Y represents NR 3 , R 1 and R 3 may together represent —CH 2 —;
  • R 2 represents a hydrocarbon group of 1-10 carbon atoms which is optionally substituted with up to 3 halogen atoms, or heteroaryl of 5 or 6 ring atoms optionally bearing up to 3 substituents independently selected from halogen, CF 3 , CHF 2 , CH 2 F, NO 2 , CN, OCF 3 , C 1-6 alkyl and C 1-6 alkoxy; or when Y represents NR 3 , R 2 and R 3 together may complete a heterocyclic ring of up to 6 members which optionally bears up to 3 substituents independently selected from halogen, CF 3 , CHF 2 , CH 2 F, NO 2 , CN, OCF 3 , C 1-6 alkyl and C 1-6 alkoxy;
  • R 3 represents H or C 1-4 alkyl, or together with R 1 represents —CH 2 —, or together with R 2 completes a heterocyclic ring as defined above;
  • R 4 represents halogen or C 1-4 alkyl
  • variable occurs more than once in formula I or in a substituent thereof, the individual occurrences of that variable are independent of each other, unless otherwise specified.
  • hydrocarbon group refers to groups consisting solely of carbon and hydrogen atoms. Such groups may comprise linear, branched or cyclic structures, singly or in any combination consistent with the indicated maximum number of carbon atoms, and may be saturated or unsaturated, including aromatic when the indicated maximum number of carbon atoms so permits.
  • C 1-x alkyl where x is an integer greater than 1 refers to straight-chained and branched alkyl groups wherein the number of constituent carbon atoms is in the range 1 to x.
  • Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl and t-butyl.
  • Derived expressions such as “C 2-6 alkenyl”, “hydroxyC 1-6 alkyl”, “heteroarylC 1-6 alkyl”, “C 2-6 alkynyl” and “C 1-6 alkoxy” are to be construed in an analogous manner. Most suitably, the number of carbon atoms in such groups is not more than 6.
  • C 3-6 cycloalkyl refers to nonaromatic monocyclic hydrocarbon ring systems comprising from 3 to 6 ring atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclohexenyl.
  • cycloalkylalkyl as used herein includes groups such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.
  • halogen as used herein includes fluorine, chlorine, bromine and iodine, of which fluorine and chlorine are preferred.
  • the compounds of formula I may be in the form of pharmaceutically acceptable salts.
  • Other salts may, however, be useful in the preparation of the compounds of formula I or of their pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, benzenesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, benzenesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tart
  • a pharmaceutically acceptable salt may be formed by neutralisation of said acidic moiety with a suitable base.
  • suitable bases such as amine salts (including pyridinium salts) and quaternary ammonium salts.
  • the compounds according to the invention may accordingly exist as enantiomers. Where the compounds according to the invention possess two or more asymmetric centres, they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present invention.
  • X completes a 5- or 6-membered heteroaromatic ring bearing the group Ar as a substituent, and optionally the group R 5 as a substituent.
  • Five-membered rings completed by X preferably comprise at least one heteroatom, selected from O, N and S, in addition to the nitrogen atom shown in formula 1.
  • Suitable five-membered rings include pyrazole, oxazole, isoxazole, thiazole, isothiazole, imidazole, triazole, oxadiazole and thiadiazole, of which pyrazole, oxazole, thiazole, imidazole and 1,2,4-triazole are preferred.
  • Suitable 6-membered rings include pyridine, pyrimidine and pyrazine, of which pyridine is preferred.
  • the optional substituent R 5 is a hydrocarbon group of 1-5 carbon atoms which is optionally substituted with up to 3 halogen atoms, and thus may comprise cyclic or acyclic hydrocarbon residues or combinations thereof, saturated or unsaturated, up to a maximum of 5 carbon atoms in total.
  • the hydrocarbon group represented by R 5 is preferably unsubstituted or is substituted with up to 3 fluorine atoms
  • Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclopropylmethyl and allyl.
  • Preferred examples include methyl, ethyl and 2,2,2-trifluoroethyl.
  • R 5 represents methyl.
  • R 5 may be attached to a ring carbon atom or to a ring nitrogen atom when valency constraints so permit, including to the nitrogen atom shown in formula I although this is not preferred.
  • Ar represents phenyl or 6-membered heteroaryl, either of which bears 0-3 substituents independently selected from halogen, CF 3 , CHF 2 , CH 2 F, NO 2 , CN, OCF 3 , C 1-6 alkyl and C 1-6 alkoxy.
  • suitable 6-membered heteroaryl groups represented by Ar include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl and triazinyl, of which pyridyl is a preferred example.
  • the phenyl or heteroaryl ring bears 0 to 2 substituents.
  • Preferred substituents include halogen (especially chlorine and fluorine), CN, C 1-6 alkyl (especially methyl), C 1-6 alkoxy (especially methoxy), OCF 3 and CF 3 . If two or more substituents are present, preferably not more than one of them is other than halogen or alkyl.
  • groups represented by Ar include phenyl, monohalophenyl, dihalophenyl, trihalophenyl, cyanophenyl, methylphenyl, methoxyphenyl, trifluoromethylphenyl, trifluoromethoxyphenyl, pyridyl, monohalopyridyl and trifluoromethylpyridyl, wherein “halo” refers to fluoro or chloro.
  • Suitable specific values for Ar include 2-fluorophenyl, 2-chlorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluorophenyl, 3,4,5-trifluorophenyl, 4-cyanophenyl, 4-methylphenyl, 4-methoxyphenyl, 2-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazin-2-yl, 5-methylpyridin-2-yl, 5-fluoropyridin-2-yl, 5-chloropyridin-2-yl, 5-(trifluoromethyl)pyr
  • Preferred examples include 2-fluorophenyl, 2-chlorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluorophenyl, 4-(trifluoromethyl)phenyl, pyridin-2-yl, pyridin-3-yl and pyridin-4-yl.
  • Ar represents 4-fluorophenyl.
  • Ar may be attached to a ring carbon or ring nitrogen, preferably in a 1,3-relationship to the double bond which links the ring completed by X to the remainder of the molecule.
  • heteroaryl groups completed by X include 5-aryl-1-methylpyrazol-3-yl, 5-aryloxazol-2-yl, 4-arylpyridin-2-yl, 1-arylimidazol-4-yl, and 1-aryl-[1,2,4]triazol-3-yl, where “aryl” refers to the group Ar having the definition and preferred identities indicated above.
  • a particularly preferred example is 5-(4-fluorophenyl)-1-methylpyrazol-3-yl.
  • R 4 represents halogen (especially Cl, Br or I) or C 1-4 alkyl, such as methyl, ethyl, isopropyl, n-propyl or n-butyl.
  • R 4 represents Cl or methyl.
  • R 4 represents Cl.
  • Y represents a bond or NR 3 .
  • R 3 optionally combines with R 1 to form a —CH 2 — group. Otherwise, R 1 is H.
  • R 1 and R 3 combine in this manner, the result is a spiro-linked cyclic sulfamide of formula II:
  • n, X, R 2 , R 4 , R 5 and Ar have the same definitions and preferred identities as before.
  • R 2 represents an optionally-substituted hydrocarbon group as defined previously.
  • Suitable hydrocarbon groups represented by R 2 include alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, phenyl and benzyl groups optionally bearing up to 3 halogen substituents, the preferred halogen substituent being fluorine or chlorine, especially fluorine.
  • Said alkyl, cycloalkyl, cycloalkylalkyl and alkenyl groups typically comprise up to 6 carbon atoms.
  • hydrocarbon and fluorinated hydrocarbon groups represented by R 2 include 4-fluorophenyl, benzyl, n-propyl, 2,2-dimethylpropyl, n-butyl, isopropyl, t-butyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, allyl, 2-methylpropen-3-yl, cyclopropyl, cyclobutyl, cyclopentyl and cyclopropylmethyl.
  • Heteroaryl groups represented by R 2 are either 5-membered or 6-membered and are optionally substituted as defined previously.
  • Preferred 5-membered heteroaryl groups include those containing a sulphur atom, such as thienyl, thiathiazolyl and isothiazolyl.
  • Preferred 6-membered heteroaryl groups include pyridyl, in particular 3-pyridyl.
  • Preferred substituents include halogen (especially chlorine or fluorine), CF 3 and allyl (such as methyl). If two or more substituents are present, preferably not more than one of them is other than halogen or alkyl.
  • Preferred heteroaryl groups are unsubstituted or monosubstituted with halogen.
  • R 2 represents an optionally substituted phenyl or heteroaryl group
  • Y is preferably a bond.
  • R 2 may combine with R 3 to complete a heterocyclic ring of up to 6 members which is optionally substituted as defined previously.
  • Said ring preferably comprises at most one heteroatom selected from O, N and S in addition to the nitrogen to which R 2 and R 3 are mutually attached.
  • Suitable rings include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl.
  • Preferred substituents include CF 3 , halogen (especially chlorine or fluorine) and alkyl such as methyl. If two or more substituents are present, preferably not more than one of them is other than halogen or alkyl.
  • R 3 may alternatively represent H or C 1-4 alkyl, such as methyl.
  • R 3 represents H or completes a ring with R 2 or with R 1 .
  • Y is a bond and R 2 is hydrocarbon of up to 6 carbon atoms, optionally bearing up to 3 fluorine or chlorine substituents, or 5- or 6-membered heteroaryl which is optionally substituted as described previously.
  • suitable identities for R 2 include methyl, n-butyl, 4-fluorophenyl, 2-thienyl, 5-chloro-2-thienyl, 5-isothiazolyl and 6-chloro-3-pyridyl.
  • Preferred identities for R 2 include 6-chloro-3-pyridyl.
  • Y is NH and R 2 represents alkyl, alkenyl, cycloalkyl or cycloalkylalkyl of up to 6 carbon atoms which is optionally substituted with up to 3 fluorine atoms.
  • R 2 represents alkyl, alkenyl, cycloalkyl or cycloalkylalkyl of up to 6 carbon atoms which is optionally substituted with up to 3 fluorine atoms.
  • preferred identities for R 2 include n-propyl, n-butyl, 2-methylpropen-3-yl, cyclobutyl and 2,2,2-trifluoroethyl.
  • Y represents NR 3 and R 2 and R 3 complete a heterocyclic ring as described previously, in particular a pyrrolidine ring.
  • a fourth subset of the compounds of formula I is defined by formula II above in which R 2 represents alkyl, alkenyl, cycloalkyl or cycloalkylalkyl of up to 6 carbon atoms which is optionally substituted with up to 3 fluorine atoms.
  • suitable identities for R 2 include, n-propyl, 2,2-dimethylpropyl, n-butyl, isopropyl, t-butyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, allyl, cyclobutyl and cyclopropylmethyl, in particular allyl, cyclopropylmethyl, n-propyl, n-butyl, cyclobutyl and 2,2,2-trifluoroethyl.
  • the compounds of the present invention have an activity as inhibitors of ⁇ secretase.
  • compositions comprising one or more compounds of this invention and a pharmaceutically acceptable carrier.
  • these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, transdermal patches, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
  • the principal active ingredient typically is mixed with a pharmaceutical carrier, e.g.
  • a tableting ingredient such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate and dicalcium phosphate, or gums, dispersing agents, suspending agents or surfactants such as sorbitan monooleate and polyethylene glycol, and other pharmaceutical diluents, e.g. water, to form a homogeneous preformulation composition containing a compound of the present invention, or a pharmaceutically acceptable salt thereof.
  • these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.
  • Typical unit dosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient.
  • Tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, liquid- or gel-filled capsules, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, poly(ethylene glycol), poly(vinylpyrrolidone) or gelatin.
  • the present invention also provides a compound of the invention or a pharmaceutically acceptable salt thereof for use in a method of treatment of the human body.
  • the treatment is for a condition associated with the deposition of ⁇ -amyloid.
  • the condition is a neurological disease having associated ⁇ -amyloid deposition such as Alzheimer's disease.
  • the present invention further provides the use of a compound of the present invention or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing Alzheimer's disease.
  • a suitable dosage level is about 0.01 to 250 mg/kg per day, preferably about 0.01 to 100 mg/kg per day, more preferably about 0.05 to 50 mg/kg of body weight per day, and for the most preferred compounds, about 0.1 to 10 mg/kg of body weight per day.
  • the compounds may be administered on a regimen of 1 to 4 times per day. In some cases, however, a dosage outside these limits may be used.
  • n, X, R 2 , R 4 , R 5 and Ar have the same meanings as before.
  • the reaction may be carried out in DMSO at 100° C. in a sealed tube.
  • the compounds of formula II may be obtained by sequential treatment of an aziridine of formula (1b) with an amine R 2 NH 2 and then NH 2 SO 2 NH 2 .
  • Reaction of (1b) with the amine may be carried out in refluxing dichloromethane in the presence of zinc iodide, and reaction of the resulting diamine may with sulfamide may be carried out in refluxing pyridine.
  • Aziridines (1a) may be prepared by condensation of ketones (2) with Me 2 NSO 2 NH 2 and reaction of the resulting sulphimine with trimethylsulfoxonium iodide:
  • n, X, R 4 , R 5 and Ar have the same meanings as before.
  • the condensation may be carried out in refluxing THF in the presence of Ti(OEt) 4 , while reaction to form the aziridine (1) takes place in DMSO at ambient temperature in the presence of sodium hydride.
  • Aziridines (1b) may be prepared in the same manner, substituting tBuSONH 2 for Me 2 NSO 2 NH 2 .
  • R 2 , Y, n, X, R 4 , R 5 and Ar have the same meanings as before.
  • the reaction may be carried out in an aprotic solvent such as dichloromethane in the presence of a base such as triethylamine.
  • a base such as triethylamine.
  • amine (3) may be treated sequentially with catechol sulphate and R 2 R 3 NH, in the manner described in WO 02/36555.
  • Amines (3) may be prepared by condensation of ketones (2) with tBuSONH 2 as described above, followed by reduction of the resulting sulfinimide with sodium borohydride (e.g. in methanol solution at 0° C.), then hydrolysis of the resulting sulfinamide (e.g. by treatment with HCl in dioxan and methanol at 0° C.).
  • the ketones (2) may be prepared by reaction of aldehydes (4) with phosphonium salts (5) in the presence of strong base, followed by hydrolysis of the cyclic ketal group:
  • Hal represents halogen (preferably Cl, Br or I and n, X, Ar, R 4 and R 5 have the same meanings as before.
  • the reaction may be carried out in an aprotic solvent such as THF at 0° C. in the presence of n-BuLi.
  • Hydrolysis of the cyclic ketal may be effected by treatment with dilute HCl in THF at 60° C.
  • Aldehydes (4) in which R 4 is Cl may be prepared by reaction of ketone (6) with POCl 3 and dimethylformamide (DMF):
  • the POCl 3 and DMF are typically pre-reacted in dichloromethane solution at 0° C., then refluxed with the ketone in the same solvent.
  • Aldehydes of formula (4) where R 4 is C 1-4 alkyl may be prepared by treatment of the corresponding chlorides (4) (R 4 ⁇ Cl) with the appropriate alkylcopper derivative in THF at ⁇ 78° C.
  • the alkylcopper reagent may be prepared in situ by pre-reaction of the corresponding alkyllithium with CuI at 0° C.
  • Ketone (6) may be obtained from bicyclo[4,2,1]non-3-en-9-one (7) by (i) formation of the cyclic ketal, (ii) hydroboration, and (iii) oxidation of the of the resulting cycloalkanols, as described in the Examples included herein.
  • R 2 and R 4 have the same meanings as before.
  • the reaction takes place under the same conditions as the reaction of (5) with (4).
  • Compounds (8) may be obtained from compound (7) via elaboration of its ketone group in the manner described previously for the conversion of ketones (2) to compounds of formula II, followed by hydroboration, oxidation and treatment with POCl 3 and DMF as described above for the conversion of (7) to (4).
  • Phosphonium salts (5) may be obtained by reaction of halides (9)(a) with Ph 3 P, e.g. in refluxing xylene, while halides (9)(a) are available by conventional routes. In one such route, alcohols (9)(b) are treated with thionyl chloride in dichloromethane at ambient temperature. Alcohols (9)(b) may be prepared by reduction of aldehydes (10), e.g. using sodium borohydride in ethanol:
  • Aldehydes (10) may be prepared by conventional techniques of heterocyclic synthesis, as illustrated in the Examples section.
  • novel compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
  • the novel compounds may, for example, be resolved into their component enantiomers by standard techniques such as chiral HPLC, or the formation of diastereomeric pairs by salt formation with an optically active acid, such as di-p-toluoyl-D-tartaric acid and/or di-p-toluoyl-L-tartaric acid, followed by fractional crystallization and regeneration of the free base.
  • the novel compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, such techniques may be carried out on racemic synthetic precursors of the compounds of interest.
  • the starting materials and reagents used in the above-described synthetic schemes may be prepared by conventional means.
  • any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1999.
  • the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • the compounds of the present invention show unexpectedly high affinities as measured by the above assays.
  • the following Examples all had an ED 50 of less than 100 nM, typically less than 10 nM, and frequently less than 1 nM in at least one of the above assays.
  • the compounds also exhibit good oral bioavailability and/or brain penetration, and are largely free from undesirable biological interactions likely to lead to toxic side effects.
  • the aldehyde from Step 2 (2.3 g, 11 mmol) was dissolved in ethanol and sodium borohydride (0.832 g, 22 mmol) added, and the reaction stirred at 25° C. for 1 h.
  • the reaction was quenched with ammnonium chloride solution, the ethanol removed in vacuo and the aqueous extracted into ethyl acetate (2 ⁇ ), washed with brine and concentrated to give a yellow oil.
  • the crude alcohol was dissolved in dichloromethane (20 mL), thionyl chloride ( 1.6 mL, 22 mmol) was added and the reaction stirred at 25° C. for 1 h.
  • Trimethylsulfoxonium iodide (151.3 g, 0.69 mol) was dissolved in anhydrous DMSO (660 mL) under nitrogen and sodium hydride (60% dispersion in oil, 27.5 g, 0.687 mol) added in portions. The reaction was stirred until hydrogen evolution ceased, then the oil from (a) was added as a solution in DMSO and the mixture stirred at 25° C. for 2 h. The reaction mixture was poured into water (1. 1 L) and ether (1.1 L). The phases were separated and the aqueous layer extracted with ether (2 ⁇ 550 mL). The combined organic layers were washed with brine, dried over magnesium sulfate and evaporated in vacuo.
  • Step 1 The product of Step 1 ( 6.6 g, 0.021 mol) was dissolved in acetone (100 mL) and potassium carbonate ( 4.3 g, 0.031 mol) was added, followed by tetra-n-butylammonium iodide (0.760 g, 2.05 mmol) and p-methoxybenzyl chloride (6.4 g, 0.041 mol). The reaction was stirred at 25° C. under nitrogen for 36 h., filtered and the filtrate was concentrated in vacuo. The residue was recrystallised from ethyl acetate/hexane to obtain a white solid (tetra-n-butylammonium iodide).
  • Step 2 The product of Step 2 ( 5.65 g, 0.013 mol) was dissolved in anhydrous THF, cooled to 0° C. and borane (1M solution in TBF, 26 mL, 0.026 mol) was added dropwise. The reaction was warmed to 25° C. and then heated to reflux for 2 h. The flask was once again cooled to 0° C. and NaOH (4M, 19.5 mL, 0.078 mol) was added dropwise, followed by hydrogen peroxide (35% w/w, 7.6 mL, 0.078 mol). The reaction was stirred at 25° C. for 16 h.
  • reaction mixture was partitioned between water and ethyl acetate and the organic layer was washed with water and brine, dried over MgSO 4 , and the solvent evaporated.
  • the residual oil was chromatographed on silica eluting with 50%-60% ethyl acetate/hexane to provide the title compound (mixture of epimers) as a colourless oil.
  • Step 3 The product of Step 3 (4.6 g, 0.01 mol) was dissolved in dichloromethane (200 mL) and molecular sieves (4 ⁇ , 2.5 g) were added followed by N-methylmorpholine N-oxide (1.8 g, 0.015 mol) and tetrapropylammonium perruthenate (0.151 g, 0.042 mmol). The reaction mixture was stirred under nitrogen for 1.5 h, diluted with ethyl acetate and filtered through a pad of silica with further washings with ethyl acetate.
  • Step 6 The product of Step 6 (0.04 g, 0.006 mmol) was treated with trifluoroacetic acid (3 mL) and the mixture was stirred at 25° C. for 2 h. The reaction mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and saturated sodium bicabonate solution. The organic layer was collected, washed with brine, dried over MgSO 4 and evaporated. The residue was chromatographed on silica eluting with 50%-70% ethyl acetate/hexanes to obtain the product as a white solid.
  • Methyllithium (1.6M in ether, 9 mL, 14 mmol) was added to a suspension of CuI (1.33 g, 7 mmol) in TBF (5 ml) at 0° C. The reaction was stirred at 0° C. for 10 minutes and warmed briefly to 10° C. and then cooled to ⁇ 78° C. The product of Example 1, Step 5 (2.46 g, 5 mmol) in THF (10 mL) was added and the reaction stirred for 1 h at ⁇ 78° C. The reaction was quenched with ammonium chloride solution and the product extracted into ethyl acetate. The organic layer was dried over MgSO 4 and evaporated.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Neurosurgery (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biomedical Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Neurology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Steroid Compounds (AREA)
  • Enzymes And Modification Thereof (AREA)
  • Saccharide Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
US10/566,486 2003-08-05 2004-07-29 Gamma-secretase inhibitors Expired - Fee Related US7452899B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB03184470 2003-08-05
GBGB0318447.0A GB0318447D0 (en) 2003-08-05 2003-08-05 Therapeutic agents
PCT/GB2004/003277 WO2005014553A1 (fr) 2003-08-05 2004-07-29 Nouveaux inhibiteurs de l'enzyme gamma-secretase

Publications (2)

Publication Number Publication Date
US20060189666A1 US20060189666A1 (en) 2006-08-24
US7452899B2 true US7452899B2 (en) 2008-11-18

Family

ID=27839748

Family Applications (1)

Application Number Title Priority Date Filing Date
US10/566,486 Expired - Fee Related US7452899B2 (en) 2003-08-05 2004-07-29 Gamma-secretase inhibitors

Country Status (11)

Country Link
US (1) US7452899B2 (fr)
EP (1) EP1658272B1 (fr)
JP (1) JP4714686B2 (fr)
CN (1) CN100475792C (fr)
AT (1) ATE368031T1 (fr)
AU (1) AU2004263353B2 (fr)
CA (1) CA2534057A1 (fr)
DE (1) DE602004007808T2 (fr)
ES (1) ES2289537T3 (fr)
GB (1) GB0318447D0 (fr)
WO (1) WO2005014553A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011006144A1 (fr) 2009-07-10 2011-01-13 Martek Biosciences Corporation Procédés de traitement et de prévention de troubles neurologiques à l'aide de l'acide docosahexaénoique

Families Citing this family (62)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7521481B2 (en) 2003-02-27 2009-04-21 Mclaurin Joanne Methods of preventing, treating and diagnosing disorders of protein aggregation
AR047666A1 (es) * 2004-02-20 2006-02-01 Merck Sharp & Dohme Sintesis estereoselectiva del acido ciclohexanopropanoico 4,4-disubstituido
WO2006123182A2 (fr) 2005-05-17 2006-11-23 Merck Sharp & Dohme Limited Sulfones de cyclohexyle pour le traitement du cancer
EP1996182A4 (fr) 2006-02-27 2009-08-12 Univ Johns Hopkins Traitement anticancéreux utilisant des inhibiteurs de gamma-sécrétases
JP5087616B2 (ja) 2006-05-31 2012-12-05 エフ．ホフマン−ラ ロシュ アーゲー アリール−４−エチニル−イソオキサゾール誘導体
WO2008055945A1 (fr) 2006-11-09 2008-05-15 Probiodrug Ag Dérivés 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one utiles en tant qu' inhibiteurs de la glutaminyl-cyclase dans le traitement des ulcères, du cancer et d'autres maladies
CA2669693C (fr) 2006-11-15 2018-06-12 Massachusetts Eye & Ear Infirmary Generation de cellules de l'oreille interne
EP2091948B1 (fr) 2006-11-30 2012-04-18 Probiodrug AG Nouveaux inhibiteurs de glutaminylcyclase
EP2121633A2 (fr) 2007-02-12 2009-11-25 Merck & Co., Inc. Dérivés de pipérazine pour le traitement de la maladie d'alzheimer et des conditions apparentées
MX2009009234A (es) 2007-03-01 2009-12-01 Probiodrug Ag Uso nuevo de inhibidores de ciclasa de glutaminilo.
EP2865670B1 (fr) 2007-04-18 2017-01-11 Probiodrug AG Dérivés de thio-urée utilisés comme inhibiteurs de la glutaminyl cyclase
WO2009000662A1 (fr) 2007-06-22 2008-12-31 F. Hoffmann-La Roche Ag Dérivés d'isoxazole-imidazole
US7618973B2 (en) 2007-12-04 2009-11-17 Hoffmann-La Roche Inc. Isoxazolo-pyrazine derivatives
US7902201B2 (en) 2007-12-04 2011-03-08 Hoffmann-La Roche Inc. Isoxazolo-pyrazine derivatives
US7943619B2 (en) 2007-12-04 2011-05-17 Hoffmann-La Roche Inc. Isoxazolo-pyridazine derivatives
WO2009128057A2 (fr) 2008-04-18 2009-10-22 UNIVERSITY COLLEGE DUBLIN, NATIONAL UNIVERSITY OF IRELAND, DUBLIN et al Produits psycho-pharmaceutiques
US10143711B2 (en) 2008-11-24 2018-12-04 Massachusetts Eye & Ear Infirmary Pathways to generate hair cells
TW201033201A (en) 2009-02-19 2010-09-16 Hoffmann La Roche Isoxazole-isoxazole and isoxazole-isothiazole derivatives
US8389550B2 (en) 2009-02-25 2013-03-05 Hoffmann-La Roche Inc. Isoxazoles / O-pyridines with ethyl and ethenyl linker
WO2010114780A1 (fr) 2009-04-01 2010-10-07 Merck Sharp & Dohme Corp. Inhibiteurs de l'activité akt
US8222246B2 (en) 2009-04-02 2012-07-17 Hoffmann-La Roche Inc. Substituted isoxazoles
US8227461B2 (en) 2009-04-30 2012-07-24 Hoffmann-La Roche Inc. Isoxazoles
MX2011011273A (es) 2009-05-05 2011-11-04 Hoffmann La Roche Derivados de isoxazol-pirazol.
SG175780A1 (en) 2009-05-05 2011-12-29 Hoffmann La Roche Isoxazole-pyridazine derivatives
KR101367012B1 (ko) 2009-05-05 2014-03-14 에프. 호프만-라 로슈 아게 이속사졸-피리딘 유도체
CA2759598C (fr) 2009-05-05 2017-09-12 F. Hoffmann-La Roche Ag Derives d'isoxazole-thiazole comme agonistes inverses du recepteur gaba a, utiles dans le traitement de troubles cognitifs
AU2010244555A1 (en) 2009-05-07 2011-11-03 F. Hoffmann-La Roche Ag Isoxazole-pyridine derivatives as GABA modulators
ES2548913T3 (es) 2009-09-11 2015-10-21 Probiodrug Ag Derivados heterocíclicos como inhibidores de glutaminil ciclasa
WO2011046771A1 (fr) 2009-10-14 2011-04-21 Schering Corporation Pipéridines substituées qui accroissent l'activité de p53, et utilisations de ces composés
ES2586231T3 (es) 2010-03-03 2016-10-13 Probiodrug Ag Inhibidores de glutaminil ciclasa
AU2011226074B2 (en) 2010-03-10 2015-01-22 Vivoryon Therapeutics N.V. Heterocyclic inhibitors of glutaminyl cyclase (QC, EC 2.3.2.5)
EP2560953B1 (fr) 2010-04-21 2016-01-06 Probiodrug AG Inhibiteurs de glutaminyl cyclase
EP2584903B1 (fr) 2010-06-24 2018-10-24 Merck Sharp & Dohme Corp. Nouveaux composés hétérocycliques utilisés comme inhibiteurs de erk
WO2012018754A2 (fr) 2010-08-02 2012-02-09 Merck Sharp & Dohme Corp. Inhibition à médiation par interférence arn de caténine (protéine associée à cadhérine), expression du gène bêta 1 (ctnnb1) à l'aide de petit acide nucléique interférent (sian)
EP3587574B1 (fr) 2010-08-17 2022-03-16 Sirna Therapeutics, Inc. Inhibition médiée par des arn interférents de l'expression génique du virus de l'hépatite b (vhb) à l'aide de petits acides nucléiques interférents (pani)
WO2012030685A2 (fr) 2010-09-01 2012-03-08 Schering Corporation Dérivés d'indazole utilisables en tant qu'inhibiteurs de la voie erk
US9242981B2 (en) 2010-09-16 2016-01-26 Merck Sharp & Dohme Corp. Fused pyrazole derivatives as novel ERK inhibitors
EP2632472B1 (fr) 2010-10-29 2017-12-13 Sirna Therapeutics, Inc. Inhibition facilitée par l'interférence d'arn de l'expression d'un gène au moyen d'acides nucléiques interférents courts (sina)
WO2012087772A1 (fr) 2010-12-21 2012-06-28 Schering Corporation Dérivés d'indazole utiles en tant qu'inhibiteurs de erk
US8530670B2 (en) 2011-03-16 2013-09-10 Probiodrug Ag Inhibitors
EP2749882B1 (fr) 2011-08-24 2017-05-03 Eiken Kagaku Kabushiki Kaisha Dispositif et trousse de réactifs pour la mesure de leucocytes
US8785435B2 (en) 2011-10-20 2014-07-22 Hoffmann-La Roche Inc. Solid forms
US9023865B2 (en) 2011-10-27 2015-05-05 Merck Sharp & Dohme Corp. Compounds that are ERK inhibitors
EP3919620A1 (fr) 2012-05-02 2021-12-08 Sirna Therapeutics, Inc. Compositions d'acide nucléique interférent court (sina)
EP3970725A1 (fr) 2012-09-07 2022-03-23 Massachusetts Eye & Ear Infirmary Un inhibiteur de la gamma-sécrétase pour le traitement de la perte auditive
US9233979B2 (en) 2012-09-28 2016-01-12 Merck Sharp & Dohme Corp. Compounds that are ERK inhibitors
PL2925888T3 (pl) 2012-11-28 2018-03-30 Merck Sharp & Dohme Corp. Kompozycje i sposoby do stosowania w leczeniu nowotworów
CA2895504A1 (fr) 2012-12-20 2014-06-26 Merck Sharp & Dohme Corp. Imidazopyridines substituees en tant qu'inhibiteurs de hdm2
WO2014120748A1 (fr) 2013-01-30 2014-08-07 Merck Sharp & Dohme Corp. Purines 2,6,7,8-substituées utilisées en tant qu'inhibiteurs de hdm2
US20160194368A1 (en) 2013-09-03 2016-07-07 Moderna Therapeutics, Inc. Circular polynucleotides
WO2016022776A2 (fr) 2014-08-06 2016-02-11 Massachusetts Eye And Ear Infirmary Augmentation de la durée de vie d'atoh1 pour diriger la différenciation des cellules ciliées neurosensorielles
WO2017096233A1 (fr) 2015-12-04 2017-06-08 Massachusetts Eye And Ear Infirmary Traitement de perte auditive par inhibition de la caséine kinase 1
KR20180117628A (ko) 2016-01-29 2018-10-29 매사추세츠 아이 앤드 이어 인퍼머리 내이 지지 세포의 확장 및 분화 및 그의 사용 방법
EP3458076A4 (fr) 2016-05-16 2020-01-22 The General Hospital Corporation Cellules souches de voies respiratoires humaines en ingénierie épithéliale pulmonaire
JP6904612B2 (ja) 2016-12-16 2021-07-21 パイプライン セラピューティクス， インコーポレイテッド 蝸牛シナプス障害を処置する方法
DK3461819T3 (da) 2017-09-29 2020-08-10 Probiodrug Ag Inhibitorer af glutaminylcyklase
US10947234B2 (en) 2017-11-08 2021-03-16 Merck Sharp & Dohme Corp. PRMT5 inhibitors
US11993602B2 (en) 2018-08-07 2024-05-28 Merck Sharp & Dohme Llc PRMT5 inhibitors
US11981701B2 (en) 2018-08-07 2024-05-14 Merck Sharp & Dohme Llc PRMT5 inhibitors
CA3160153A1 (fr) 2019-12-17 2021-06-24 Michelle Machacek Inhibiteurs de prmt5
WO2024049931A1 (fr) 2022-09-02 2024-03-07 Merck Sharp & Dohme Llc Compositions pharmaceutiques à base d'inhibiteurs de la topoisomérase-1 dérivés de l'exatécan, et leurs utilisations
WO2024091437A1 (fr) 2022-10-25 2024-05-02 Merck Sharp & Dohme Llc Charges utiles de lieur adc dérivées d'exatécan, compositions pharmaceutiques et leurs utilisations

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001070677A1 (fr) 2000-03-20 2001-09-27 Merck Sharp & Dohme Limited Dérivés de bicyxloalkyle à pontage à substitution sulphonamido
WO2002036555A1 (fr) 2000-11-02 2002-05-10 Merck Sharp & Dohme Limited Sulfamides inhibiteurs de gamma-secretase
WO2003093251A1 (fr) 2002-05-01 2003-11-13 Merck Sharp & Dohme Limited Sulfamides spirocycliques substitues par alcenyle utilises comme inhibiteurs de la gamma-secretase

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001070677A1 (fr) 2000-03-20 2001-09-27 Merck Sharp & Dohme Limited Dérivés de bicyxloalkyle à pontage à substitution sulphonamido
WO2002036555A1 (fr) 2000-11-02 2002-05-10 Merck Sharp & Dohme Limited Sulfamides inhibiteurs de gamma-secretase
WO2003093251A1 (fr) 2002-05-01 2003-11-13 Merck Sharp & Dohme Limited Sulfamides spirocycliques substitues par alcenyle utilises comme inhibiteurs de la gamma-secretase

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Dewachter et al., Lancet Neurology (2002), 1(7), 409-416. *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011006144A1 (fr) 2009-07-10 2011-01-13 Martek Biosciences Corporation Procédés de traitement et de prévention de troubles neurologiques à l'aide de l'acide docosahexaénoique

Also Published As

Publication number Publication date
GB0318447D0 (en) 2003-09-10
AU2004263353A1 (en) 2005-02-17
ATE368031T1 (de) 2007-08-15
DE602004007808T2 (de) 2008-04-17
ES2289537T3 (es) 2008-02-01
JP4714686B2 (ja) 2011-06-29
EP1658272A1 (fr) 2006-05-24
CA2534057A1 (fr) 2005-02-17
CN100475792C (zh) 2009-04-08
JP2007501206A (ja) 2007-01-25
EP1658272B1 (fr) 2007-07-25
CN1832927A (zh) 2006-09-13
US20060189666A1 (en) 2006-08-24
AU2004263353B2 (en) 2009-11-26
DE602004007808D1 (de) 2007-09-06
WO2005014553A1 (fr) 2005-02-17

Similar Documents

Publication Publication Date Title
US7452899B2 (en) Gamma-secretase inhibitors
US7514459B2 (en) Gamma-secretase inhibitors
US7435748B2 (en) Gamma-secretase inhibitors
US7144910B2 (en) Sulfonamides, sulfamates and sulfamides as gamma-secretase inhibitors
CA2503884C (fr) Sulfamides cycliques inhibiteurs de la gamma-secretase
US8338437B2 (en) Amines as small molecule inhibitors
RU2678305C1 (ru) Производные имидазопиридина в качестве модуляторов активности tnf
AU2005301626B2 (en) Carboxylic acid derivative containing thiazole ring and pharmaceutical use thereof
RU2382766C2 (ru) Производные арилсульфонилстильбена для лечения бессонницы и связанных с ней расстройств
JP4949582B2 (ja) 新規アミノチアゾール誘導体、それらの製造およびそれらを含有する医薬組成物
US6156761A (en) Substituted tetralone derivatives for enhancing cognition
US10618892B2 (en) Processes for the preparation of a BACE inhibitor
WO1998016526A1 (fr) Tetrahydro-6h-pyrazino[1,2-b]isoquilone 1,4-diones en tant qu'inhibiteurs de l'apoproteine b-100
JP2005298333A (ja) 新規トリアゾール誘導体及びこれを有効成分とする抗真菌剤

Legal Events

Date Code Title Description
AS Assignment

Owner name: MERCK SHARP & DOHME LTD., ENGLAND

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:BETTATI, MICHELA;BOASE, AMANDA LOUISE;CHURCHER, IAN;AND OTHERS;REEL/FRAME:017972/0773;SIGNING DATES FROM 20051212 TO 20060118

CC Certificate of correction
FPAY Fee payment

Year of fee payment: 4

REMI Maintenance fee reminder mailed
LAPS Lapse for failure to pay maintenance fees
STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362

FP Lapsed due to failure to pay maintenance fee

Effective date: 20161118